1. Field of the Art
This invention relates to S-adenosyl-L-methionine (hereinafter referred to as SAM) compositions comprising SAM, a sulfuric acid equivalent and a nucleoside sulfate (hereinafter referred to as an NS) and especially to the SAM-containing compositions comprising a nucleoside monosulfate (hereinafter referred to an NMS) and/or a nucleoside disulfate (hereinafter referred to as NDS) as the NS component, and to a method for preparation thereof. More specifically, this invention provides a stabilized SAM-containing composition wherein the SAM, which is very unstable in a free form or an ordinary salt form, is stabilized via chemical interaction in the copresence of a sulfuric acid equivalent and an NS.
SAM is a physiological active substance which plays an important role as a methyl group donor of methylation reaction by way of various transmethylases in vivo. For example, SAM is an indispensable substance which serves as the methyl group donor in a transmethylation reaction, e.g., methylation of high molecular substances in vivo such as nucleic acid, protein and fat, formation of creatine from guanidinoacetate, formation of choline from ethanolamine, and the like. Consequently, SAM is useful as a chemotherapeutic agent for metabolic disorders. Its therapeutic value for hepatopias, hyperdislipidemias, generalized or local arteriosclerosis, psychiatric manifestations of depressive and neutrological type, degenerative arythromathies, neurological algetic manifestation, disturbance of the sleeping-making rhythm, etc., has been reported.
From the viewpoint of practical use of SAM in medical drugs, however, SAM is very unstable even at room temperature, and a serious problem has been that SAM alone can hardly be used as a medical drug. Thus, SAM has been prepared in the form of anionic salts such as the iodide, bromide, Reinecke'salt, hydrochloride and sulfate thereof, but all these salts are unstable in storage. For example, dry SAM hydrochloride kept at 37.degree. C. in a dry condition is decomposed to about one-half is initial amount in 4 days.
2. Prior Art
As stabilized SAM salts there have recently been developed p-toluenesulfonate (cf. British Pat. No. 1,425,384); the double salt with p-toluenesulfonic acid and sulfuric acid (cf. U.S. Pat. No. 3,954,726); methanesulfonate, ethanesulfonate, 1-n-dodecanesulfonate, 1-n-dodecanesulfonate, 1-n-octadecanesulfonate, 2-chloroethanesulfonate, 2-bromoethanesulfonate, 3-hydroxypropanesulfonate, camphor-10-sulfonate, 3-bromocamphor-10-sulfonate, cysteinate, benzenesulfonate, lp-chlorobenzenesulfonate, 2-mesitylbenzenesulfonate, 4-biphenylsulfonate, 1-naphthalenesulfonate, 5-sulfosalicylate, p-acetylbenzenesulfonate, 1,2-ethanedisulfonate, o-benzenedisulfonate, chondroitin sulfate, and the double salts with these sulfonic acids and sulfuric acid (cf. U.S. Pat. No. 4,057,686).
Some of these known sulfonates or the double salts with the corresponding sulfonic acids and sulfuric acid, however, are accompanied by problems such as hygroscopic property and unsatisfactory stability and/or the necessity or resorting to complicated processes for their preparation and purification. Moreover, the corresponding sulfonic acids themselves which are contained in these salts are often irritative or poisonous. From the viewpoint of use of SAM as medical drugs, the above-mentioned sulfonates or the double salts with the sulfonic acids and sulfuric acid cannot always be said to be harmless.